This invention is in the area of methods for the treatment of human immunodeficiency virus (also referred to as xe2x80x9cHIVxe2x80x9d) that includes administering to a host in need thereof, either alone or in combination, an effective HIV-treatment amount of one or more of the active compounds disclosed herein, or a pharmaceutically acceptable prodrug or salt of one of these compounds.
In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system, and that almost without exception leads to death. In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV).
In 1985, it was reported that the synthetic nucleoside 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT) inhibits the replication of human immunodeficiency virus. Since then, a number of other synthetic nucleosides, including (xe2x88x92)-xcex2-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thiacytidine (3TC), xcex2-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thia-5-fluorocytidine (FTC), 2xe2x80x2,3xe2x80x2-dideoxyinosine (DDI), 2xe2x80x2,3xe2x80x2-dideoxycytidine (DDC), and 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine (D4T), have been proven to be effective against HIV. After cellular phosphorylation to the 5xe2x80x2-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3xe2x80x2-hydroxyl group. They can also inhibit the viral enzyme reverse transcriptase.
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that substitute a heteroatom for the carbon atom at the 3xe2x80x2-position of the nucleoside. European Patent Application Publication No. 0 337 713 and U.S. Pat. No. 5,041,449, assigned to BioChem Pharma, Inc., disclose racemic 2-substituted-4-substituted-1,3-dioxolanes that exhibit antiviral activity. U.S. Pat. No. 5,047,407 and European Patent Application Publication No. 0 382 526, also assigned to BioChem Pharma, Inc., disclose that a number of racemic 2-substituted-5-substituted-1,3-oxathiolane nucleosides have antiviral activity, and specifically report that the racemic mixture of 2-hydroxymethyl-5-(cytosin- 1-yl)- 1 ,3-oxathiolane (referred to as BCH-189) has approximately the same activity against HIV as AZT, with little toxicity. The (xe2x88x92)-enantiomer of the racemate BCH-189, known as 3TC, which is covered by U.S. Pat. No. 5,539,116 to Liotta et al., is currently sold for the treatment of HIV in humans in the U.S. in combination with AZT.
It has also been disclosed that cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (xe2x80x9cFTCxe2x80x9d) has potent HIV activity. Schinazi, et al., xe2x80x9cSelective Inhibition of Human Immunodeficiency viruses by Racemates and Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-yl] Cytosinexe2x80x9d Antimicrobial Agents and Chemotherapy, November 1992, pp. 2423-2431. See also U.S. Pat. Nos. 5,210,085; 5,814,639; 5,728,575; 5,827,727; 5,914,331; WO 91/11186 and WO 92/14743.
WO 96/40164 filed by Emory University, UAB Research Foundation, and the Centre National de la Recherche Scientifique discloses a number of xcex2-L-2xe2x80x2,3xe2x80x2-dideoxynucleosides for the treatment of hepatitis B.
WO 95/07287 also filed by Emory University, UAB Research Foundation, and the Centre National de la Recherche Scientifique discloses 2xe2x80x2 or 3xe2x80x2 deoxy and 2xe2x80x2,3xe2x80x2-dideoxy-xcex2-L-pentofuranosyl nucleosides for the treatment of HIV infection.
W096/13512 filed by Genencor International, Inc., and Lipitek, Inc., discloses the preparation of L-ribofuranosyl nucleosides as antitumor agents and virucides.
WO 095/32984 discloses lipid esters of nucleoside monophosphates as immunosuppresive drugs,
DE4224737 discloses cytosine nucleosides and their pharmaceutical uses.
Tsai, et al., in Biochem. Pharmacol. 48(7), pages 1477-81, 1994 discloses the effect of the anti-HIV agent 2xe2x80x2-xcex2-D-F-2xe2x80x2,3xe2x80x2-dideoxynucleoside analogs on the cellular content of mitochondrial DNA and lactate production.
Galvez, J. Chem. Inf. Comput. Sci. (199 4), 35(5), 1198-203 describes molecular computation of xcex2-D-3xe2x80x2-azido,-2xe2x80x2,3xe2x80x2-dideoxy-5-fluorocytidine.
Mahmoudian, Pharm. Research 8(1), 43-6 (1991) discloses quantitative structure-activity relationship analyses of HIV agents such as xcex2-D-3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxy-5-fluorocytidine.
U.S. Pat. No. 5,703,058 discloses (5-carboximido or 5-fluoro)-(2xe2x80x2,3xe2x80x2-unsaturated or 3xe2x80x2-modified) pyrimidine nucleosides for the treatment of HIV and HBV infection.
Lin, et al., discloses the synthesis and antiviral activity of various 3xe2x80x2-azido analogues of xcex2-D-nucleosides in J. Med. Chem. 31(2), 336-340 (1988).
In light of the fact that acquired immune deficiency syndrome and AIDS-related complex have reached epidemic levels worldwide, and have tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat these diseases that have low toxicity to the host.
It is an object of the present invention to provide a compound and method for the treatment of human patients or other host animals infected with HIV.
A method for the treatment of HIV infection in humans and other host animals is disclosed that includes administering an effective HIV-treatment amount to the host of a xcex2-L-(2xe2x80x2or 3xe2x80x2-azido)-2xe2x80x2,3xe2x80x2-dideoxy-5-fluorocytosine nucleoside or a pharmaceutically acceptable salt, ester, or prodrug thereof, including a stabilized phosphate, administered either alone or in combination or alternation with another anti-HIV agent, optionally in a pharmaceutically acceptable carrier. In a preferred embodiment, the 2xe2x80x2or 3xe2x80x2-azido group is in the ribosyl configuration.
The disclosed xcex2-L-(2xe2x80x2 or 3xe2x80x2-azido)-2xe2x80x2,3xe2x80x2-dideoxy-5-fluorocytosine nucleosides, or pharmaceutically acceptable salts, esters, or prodrugs or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of HIV infections and other related conditions such as Acquired Immune Deficiency Syndrome (AIDS), AIDS-Related Complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions, anti-HIV antibody positive and HIV-positive conditions, Kaposi""s sarcoma, thrombocytopenia purpurea and opportunistic infections. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HIV antibody or HIV-antigen positive or who have been exposed to HIV.
In one embodiment, the active compound is xcex2-L-(2xe2x80x2-azido)-2xe2x80x2,3xe2x80x2-dideoxy-5-fluorocytosine (L-2xe2x80x2-A-5-FddC) or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula: 
wherein R is H, acyl, monophosphate, diphosphate, or triphosphate, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug), and Rxe2x80x2 is H, acyl, or alkyl.
In another embodiment, the active compound is xcex2-L-(3xe2x80x2-azido)-2xe2x80x2,3xe2x80x2-dideoxy-5-fluorocytosine (L-3xe2x80x2-A-5-FddC) or a pharmaceutically acceptable ester, salt or prodrug thereof of the formula: 
wherein R is H, acyl, monophosphaie, diphosphate, or triphosphate, or a gtabilized phosphate derivative (to form a stabilized nucleotide prodrug), and Rxe2x80x2 is H, acyl, or alkyl.
In another embodiment, the L-(2xe2x80x2 or 3xe2x80x2)-A-5-FddC nucleoside is administered in alternation or combination with one or more other compounds which exhibit activity against HIV, as described in more detail below. In general, during alternation therapy, an effective dosage of each agent is administered serially, whereas in combination therapy, an effective dosage of two or more agents are administered together. The dosages will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. In one preferred embodiment, the compound is administered in combination with AZDU (3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxyuridine).